really affect icu mortality? care patient (the enpic study

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Evaluation of Nutritional Practices in the CriticalCare Patient (The ENPIC Study): Does NutritionReally Affect ICU Mortality?Lluís Servia-Goixart

Hospital Universitari Arnau de VilanovaJuan Carlos Lopez-Delgado ( [email protected] )

Hospital Universitari de Bellvitge https://orcid.org/0000-0003-3324-1129Teodoro Grau-Carmona

Hospital Universitario 12 de OctubreJavier Trujillano-Cabello

Hospital Universitari Arnau de VilanovaM Luisa Bordeje-Laguna

Hospital Universitari Germans Trias i PujolEsther Mor-Marco

Hospital Universitari Germans Trias i PujolEsther Portugal-Rodriguez

Hospital Clinico Universitario de ValladolidCarol Lorencio Cárdenas

Hospital Universitari Josep TruetaJuan C Montejo-Gonzalez

Hospital Universitario 12 de OctubrePaula Vera-Artazcoz

Hospital de la Santa Creu i Sant PauLaura Macaya-Redin

Complejo Hospitalario de NavarraJuan Francisco Martinez-Carmona

Hospital Regional Universitario de MalagaRayden Iglesias-Rodriguez

Hospital General de GranollersDiana Monge-Donaire

Hospital Virgen de la ConchaJosé L Flordelis-Lasierra

Hospital Universitario Severo OchoaBeatriz Llorente-Ruiz

https://doi.org/10.21203/rs.3.rs-542565/v1

mailto:[email protected]

https://orcid.org/0000-0003-3324-1129

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Hospital Universitario Principe de AsturiasEva M Menor-Fernández

Hospital Alvaro CunqueiroItziar Martínez de Lagran

Hospital de MataroJuan C Yebenes-Reyes

Hospital de Mataro

Research

Keywords: nutritional therapy, intensive care unit, enteral nutrition, parenteral nutrition, nutritional risk,calories, protein, ENPIC

Posted Date: June 2nd, 2021

DOI: https://doi.org/10.21203/rs.3.rs-542565/v1

License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License

Version of Record: A version of this preprint was published at Clinical Nutrition ESPEN on November 1st,2021. See the published version at https://doi.org/10.1016/j.clnesp.2021.11.018.

https://doi.org/10.21203/rs.3.rs-542565/v1

https://creativecommons.org/licenses/by/4.0/

https://doi.org/10.1016/j.clnesp.2021.11.018

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AbstractBackground: The importance of arti�cial nutritional therapy is underrecognized, typically beingconsidered an adjunctive rather than a primary therapy. We aimed to evaluate the in�uence of nutritionaltherapy on mortality in critically ill patients.

Methods: This multicenter prospective observational study included adult patients needing arti�cialnutritional therapy for >48 h if they stayed in one of 38 participating intensive care units for ≥72 hbetween April and July 2018. Demographic data, comorbidities, diagnoses, nutritional status and therapy(type and details for ≤14 days), and outcomes were registered in a database. Confounders such asdisease severity, patient type (e.g., medical, surgical or trauma), and type and duration of nutritionaltherapy were also included in a multivariate analysis, and hazard ratios (HRs) and 95% con�denceintervals (95%CIs) were reported.

Results: We included 639 patients among whom 448(70.1%) and 191(29.9%) received enteral andparenteral nutrition, respectively. Mortality was 25.6%, with non-survivors having the followingcharacteristics: older age; more comorbidities; higher Sequential Organ Failure Assessment (SOFA) scores(6.6±3.3 vs 8.4±3.7; P<0.001); greater nutritional risk (Nutrition Risk in the Critically Ill [NUTRIC] score:3.8±2.1 vs 5.2±1.7; P<0.001); more vasopressor requirements (70.4% vs 83.5%; P=0.001); and more renalreplacement therapy (12.2% vs 23.2%; P=0.001). Multivariate analysis showed that older age (HR: 1.023;95% CI: 1.008–1.038; P=0.003), higher SOFA score (HR: 1.096; 95% CI: 1.036–1.160; P=0.001), higherNUTRIC score (HR: 1.136; 95% CI: 1.025–1.259; P=0.015), requiring parenteral nutrition after startingenteral nutrition (HR: 2.368; 95% CI: 1.168–4.798; P=0.017), and a higher mean Kcal/Kg/day intake (HR:1.057; 95% CI: 1.015–1.101; P=0.008) were associated with mortality. By contrast, a higher mean proteinintake protected against mortality (HR: 0.507; 95% CI: 0.263–0.977; P=0.042).

Conclusions: Old age, higher organ failure scores, and greater nutritional risk appear to be associatedwith higher mortality. Patients who need parenteral nutrition after starting enteral nutrition may representa high-risk subgroup for mortality due to illness severity and problems receiving appropriate nutritionaltherapy. Mean calorie and protein delivery also appeared to in�uence outcomes.

Trial Registration: ClinicaTrials.gov NCT: 03634943.

IntroductionThe in�ammatory response to surgery, trauma, or any severe medical condition causes metabolicdisturbances (e.g., protein catabolism) in patients admitted to intensive care units (ICUs) [1]. Inconjunction, di�culty achieving adequate nutritional targets in clinical practice may expose patients tonutritional risk or a worsening of preexisting malnutrition [2–4], both of which are associated with ahigher incidence of complications and mortality [5–7]. Nutritional therapy not only provides thesubstrates to preserve organ function but also helps modulate the in�ammatory response, optimizes themetabolic status, and ultimately provides substantial bene�t in terms of survival and outcome [5, 6].

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However, some trials have reported harmful effects, and the bene�cial effect of nutrition on mortality isunderrecognized due to these controversial results [8].

It is not always possible to provide evidence of the bene�t of nutrition in ICUs. Several factors related tonutritional therapy, such as the macronutrient dose (i.e., calories and proteins), delivery route (i.e., enteral[EN] and parenteral nutrition [PN]), and initiation time, with each having the potential to affect treatmenteffectiveness and explain the lack of positive results in some trials [5, 6]. EN is the preferred delivery routefor patients in ICU, but there is huge variation in how nutritional therapy is provided clinically. Moreover,di�culty persists in meeting the nutritional targets established in clinical practice guidelines, even inrandomized control trials (RCTs) [9–15]. Thanks to technical advances and lower rates of associatedinfection, PN is now considered as safe as EN and may provide optimal delivery of nutrients [9]. Anotherissue that affects the perceived bene�t of nutritional therapy is its duration during the ICU stay. Theimpact of nutrition may seem less important in those with shorter stays, lower nutritional risks, and lesssevere critical illness [5, 6, 16]. Thus, we must consider all these factors in clinical ICU settings whenevaluating the impact of nutrition on mortality, especially those associated with the delivery route andduration of therapy.

The primary aim of this study was to estimate the effect on mortality of the different features of arti�cialnutrition therapy during ICU stays (e.g., time of initiating nutritional support, mean energy intake, andmean protein intake). A secondary objective was to evaluate if mortality was affected by the deliveryroute (e.g., EN, PN, or both).

Method

Study populationThis multicenter prospective observational study was conducted at 38 ICUs across Spain between Apriland July 2018. Consecutive adult patients (age > 18 years) needing arti�cial nutritional therapy for > 48hours and staying in ICU for ≥ 72 hours were included. We excluded patients admitted to ICU forpostoperative recovery or ICU monitoring without needing speci�c therapy for organ support (e.g.,vasopressors or non-invasive mechanical ventilation) and those able to be fed orally.

Patients in the present study were included from the Evaluation of Nutritional Practices in the Critical Care(ENPIC) study cohort. This research re�ects a planned analysis and endpoint of this study(ClinicalTrials.gov Identi�er: NCT03634943). The observational design meant that we made no attempt toin�uence general ICU care or the nutritional approach. However, to evaluate eligibility, participatinghospitals were asked to provide information about their clinical nutrition practices and the degree ofadherence to current guidelines (e.g., presence of a nutritional protocol or the involvement of a health careprovider specializing in arti�cial nutritional support) [9].

Ethics

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A central Institutional Ethics Committee (Comité d’Ètica i Assajos Clínics de Hospital Universitari deBellvitge; Barcelona, Spain) approved the study (no. PR401/17), and the need for informed consent waswaived due to the observational design.

Data collection and de�nitionsData were extracted prospectively from the medical records of each patient and hosted in a centralizeddatabase for analysis (REDCap® electronic data at the Hospital Arnau de Vilanova, Lleida, Spain). Theentered data were cleaned from August to November 2018, and data queries were sent back to theparticipating investigators for veri�cation, after which we performed a second check and closed thedatabase in May 2020. The following general data were collected: demographics; diagnoses andcomorbidities; nutritional assessment, using the Subjective Global Assessment (SGA) and modi�edNutrition Risk in the Critically Ill (mNUTRIC) scores (without the IL-6 component); and the AcutePhysiology and Chronic Health Evaluation (APACHE) II score, the Simpli�ed Acute Physiology Score(SAPS) II, and the Sequential Organ Failure Assessment (SOFA) score on ICU admission.

Details of nutritional therapy were also collected: the time nutritional therapy was initiated, the meanenergy and protein intakes until ICU discharge or for a maximum of 14 days, and EN-relatedcomplications during their ICU stay (i.e., residual gastric volume, diarrhea, vomiting, aspiration, andmesenteric ischemia), as de�ned in the current literature [17]. Non-nutritional calories (dextrose infusionand propofol) were considered for the mean energy intake calculations. Enteral protein supplementationwas also recorded for mean protein intake calculation.

Outcomes were recorded during ICU stays, including details of hemodynamic support, renal replacementtherapies (RRT), mechanical ventilation, respiratory tract infection, and catheter-related infection. ICU andhospital mortality were followed-up for 28 days. The type of nutritional therapy was classi�ed by theroute of administration as either EN, PN, or both. The latter was classi�ed into two subgroups based onthe initial route of nutrition: EN-PN received EN initially and PN-EN received PN initially. The route waschosen by the treating medical ICU team based on the clinical indication.

To evaluate the estimate effect of different characteristics of nutrition therapy during ICU stay, wecompared subgroups based on 28-day mortality. We also compared the differences among the differenttypes of arti�cial nutritional therapies by administration route. The duration of nutritional therapy wasincluded in all analysis to add a time perspective.

Statistical analysesData are expressed as means and standard deviations, median (interquartile ranges), or numbers andpercentages, as appropriate. Analysis of variance was used to compare differences in characteristicsbetween subgroups, and the Bonferroni post-hoc test was used to determine signi�cant differences in thepairwise comparisons. The statistical analyses were conducted using IBM SPSS version 20.0 (IBM Corp.,Armonk, NY, USA), and two-tailed P-values < 0.05 were considered statistically signi�cant, unless statedotherwise.

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The Mann–Whitney U test or the two-sample t-test were used to compare between groups, as appropriate,and the χ² test was used to evaluate categorical prognostic factors in the univariate analysis. In all cases,the Kolmogorov–Smirnov test and D’Agostino–Pearson omnibus normality test were used to check thenormality of the population distribution. Survival analysis was conducted using the Kaplan–Meierestimator for each subgroup (log-rank test). Subsequent multivariate analysis was conducted using anadjusted multiple stepwise Cox regression analysis to assess the 28-day mortality. Variables wereincluded in the initial model if they had a P-value < 0.2 and were deemed suitable by the investigatorsbased on careful consideration of confounding. Investigators selected variables based on currentknowledge and literature perspective (Additional File 1: Figure S1) [18]. We used the change-in-estimatescriterion and backward deletion with a 10% cutoff to eliminate variables from the �nal model. To avoiddestabilizing the multivariate analyses, we tested for interactions between all introduced variables. Wethen adjusted for age, patient type (e.g., medical, surgical, or trauma), illness severity (e.g., APACHEscore), length of nutritional therapy, and data for which there were signi�cant differences in baselinecharacteristics between subgroups. This helped to avoid confounders and the in�uence of illness severitywhen analyzing outcomes.

ResultsData for 644 patients were included during the study, but due to the exclusion criteria and cases withincomplete data, the �nal sample comprised 639 patients (see Fig. 1). Their baseline characteristics areshown in Table 1, together with details of any nutritional therapy and clinical outcomes.

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Table 1Characteristics, nutritional support, and outcomes of the patients admitted in the ICU population.

All patients

(N = 639)

Baseline characteristics & comorbidities

Mean age (years) 61.8 ± 15

Sex (male) 432 (67.6%)

BMI (Kg·m− 2) 27.7 (27.4–28.4)

Hypertension 281 (44%)

Diabetes mellitus 164 (25.7%)

COPD 110 (17.2%)

AMI 94 (14.7%)

Chronic Liver Disease 32 (5%)

Chronic Renal Failure 68 (10.6%)

Immunosuppression 73 (11.4%)

Neoplasia 137 (21.4%)

Type of patient Medical 401 (62.8%)

Trauma 72 (11.2%)

Surgery 166 (26%)

APACHE II 20 (14–25)

SAPS II 49 ± 17.7

SOFA (on admission) 7.1 ± 3.5

Patient with malnutrition (Based on SGA) 269 (42.2%)

mNUTRIC Score 4.2 ± 2.1

Patient at risk (Based on NUTRIC Score) 287 (46%)

BMI: Body Mass Index; COPD: Chronic Obstructive Pulmonary Disease; AMI: Acute MyocardialInfarction; APACHE II: Acute Physiology and Chronic Health Disease Classi�cation System II; SAPS:Simpli�ed Acute Physiology Score; SOFA: Sequential Organ Failure Assessment; SGA: SubjectiveGlobal Assessment; mNUTRIC: modi�ed Nutrition Risk in the Critically Ill; EN: Enteral Nutrition; PN:Parenteral Nutrition; RRT: Renal Replacement Therapy; ICU: Intensive Care Unit; LOS: Length of stay.Results are expressed as mean ± standard deviation, percentage or median and interquartile range(�rst and third quartile). a During the administration of the whole nutritional therapy or at least in the�rst 14 days of nutritional therapy.

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All patients

(N = 639)

Nutrition therapy

Time of initiation of nutrition therapy (h) 28 (18–49)

Early EN (< 48h) 478 (74.8%)

Mean Kcal/Kg/day a 15.7 (15.3–16.3)

Mean g protein/Kg/day a 0.81 (0.79–0.84)

EN-related complications Any complication 161 (30.8%)

↑ GRV 81 (15.5%)

Diarrhoea 51 (9.8%)

Vomiting 8 (1.2%)

Aspiration 1 (0.2%)

Mesenteric ischemia 9 (1.7%)

Outcomes

Mechanical ventilation 583 (91.2%)

Days on mechanical ventilation 13 (12–14)

Vasoactive drug support 474 (73.9%)

RRT needs 97 (15.1%)

Respiratory tract infection 166 (25.9%)

Catheter-related infections 42 (6.6%)

Mean ICU LOS (days) 13 (8–22)

Mean hospital LOS (days) 27 (16–45)

28-day Mortality 583 (91.2%)

BMI: Body Mass Index; COPD: Chronic Obstructive Pulmonary Disease; AMI: Acute MyocardialInfarction; APACHE II: Acute Physiology and Chronic Health Disease Classi�cation System II; SAPS:Simpli�ed Acute Physiology Score; SOFA: Sequential Organ Failure Assessment; SGA: SubjectiveGlobal Assessment; mNUTRIC: modi�ed Nutrition Risk in the Critically Ill; EN: Enteral Nutrition; PN:Parenteral Nutrition; RRT: Renal Replacement Therapy; ICU: Intensive Care Unit; LOS: Length of stay.Results are expressed as mean ± standard deviation, percentage or median and interquartile range(�rst and third quartile). a During the administration of the whole nutritional therapy or at least in the�rst 14 days of nutritional therapy.

Nutritional therapy was given for a mean duration of 8 days (4–16 days). Only 95 patients (14.8%)received a short course (> 48 h to < 72 h) and only 157 (24.5%) received an intermediate course (> 72 h to

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< 7 days), whereas 387 (60.7%) received a long course (≥ 7 days). We showed differences among thesesubgroups in organ failure severity at admission; type, characteristics, and complications of nutritionalsupport; and ICU outcomes (Additional �le 2: Table S1). Patients who received a short course ofnutritional therapy received PN more frequently (hazard ratio [HR]: 1.966; 95% Con�dence Interval [CI]:1.013–3.815; P = 0.046) and exhibited lower 28-day mortality rates (HR: 0.458; 95% CI: 0.236–0.890; P = 0.021).

We classi�ed patients into four subgroups by route of nutritional therapy administration (Table 2).Overall, 118 patients (18.4%) received both EN and PN during ICU admission. Mesenteric ischemia wasobserved in 3 patients (2.5%) who received PN alone, and all 3 were related to surgical complications.

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Table 2Differences in baseline characteristics, nutrition therapy, and outcomes based on the type of route.

EN

(63.4%; n = 405)

Total PN

(18.2%; n = 116)

EN-PN

(6.7%; n = 43)

PN-EN

(11.7%; n = 75)

pvalue


Mean age (years) 60.8 ± 15 63.9 ± 14 60.2 ± 14 65.3 ± 13 0.04

Sex (male) 273(67.4%)

72 (62.1%) 31(72.1%)

56(74.7%)

0.29

BMI (Kg·m− 2) 28.2 ± 6.3 27.1 ± 5.5 27.5 ± 5.4

26.3 ± 4.7 0.04

Hypertension 172(42.5%)

55 (47.4%) 17(39.5%)

37(49.3%)

0.54

Diabetes mellitus 103(25.4%)

28 (24.1%) 13(30.2%)

20(26.7%)

0.88

COPD 73 (18%) 15 (12.9%) 9 (20.9%) 13(17.3%)

0.55

AMI 61 (15.1%) 17 (14.7%) 7 (16.3%) 9 (12%) 0.90

Chronic Liver Disease 22 (5.4%) 6 (5.2%) 0 4 (5.3%) 0.48

Chronic Renal Failure 42 (10.4%) 13 (11.2%) 3 (7%) 10(13.3%)

0.74

Immunosuppression 42 (10.4%) 15 (12.9%) 6 (14%) 10(13.3%)

0.74

Neoplasia 62 (15.3%) 45 (38.8%) 8 (18.6%) 22(29.3%)

< 0.001

Type of patient Medical 289(71.4%)

45 (38.8%) 31(72.1%)

36(48.2%)

0.01

Trauma 60 (14.8%) 2 (1.7%) 4 (9.3%) 6 (8.2%) 0.04

Surgery 56 (13.8%) 69 (59.5%) 8 (18.6%) 33 (44%) 0.07

APACHE II 20 (15–25)

19 (14–24) 20 (17–28)

20 (15–27)

0.014

BMI: Body Mass Index; COPD: Chronic Obstructive Pulmonary Disease; AMI: Acute MyocardialInfarction; APACHE II: Acute Physiology and Chronic Health Disease Classi�cation System II; SAPS:Simpli�ed Acute Physiology Score; SOFA: Sequential Organ Failure Assessment; SGA: SubjectiveGlobal Assessment; mNUTRIC: modi�ed Nutrion Risk in the Critically Ill; EN: Enteral Nutrition; PN:Parenteral Nutrition; RRT: Renal Replacement Therapy; ICU: Intensive Care Unit; NA: Not applicable.Results are expressed as mean ± standard deviation, percentage or median and interquartile range(�rst and third quartile). a During the administration of the whole nutritional therapy or at least in the�rst 14 days of nutritional therapy.

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EN

(63.4%; n = 405)

Total PN

(18.2%; n = 116)

EN-PN

(6.7%; n = 43)

PN-EN

(11.7%; n = 75)

pvalue

SAPS II 48.3 ± 17.4 48 ± 19 52.1 ± 17.1

52.8 ± 17.3

0.16

SOFA (on admission) 7.1 ± 6.1 6.1 ± 4 8.7 ± 3.6 7.8 ± 3.8 0.01

Patient with malnutrition

(based on SGA)

139(34.4%)

68 (58.1%) 17(39.5%)

45 (60%) < 0.001

mNUTRIC Score 3.9 ± 2.1 4.3 ± 1.9 4.9 ± 2.2 4.8 ± 1.8 0.02

Nutrition therapy

Time of initiation of nutritionaltherapy (h)

28 (19–48)

28 (17–63) 41 (24–71)

24 (14–47)

0.06

Early EN (< 48h) 310(76.8%)

83 (70.9%) 27(61.4%)

58(76.3%)

0.11

Days on nutrition therapy 8 (4–17) 5 (3–8) 12 (7–24)

9 (5–24) < 0.001

Mean Kcal/Kg/day a 15.4 ± 5.2 19.2 ± 7.3 14.4 ± 5.6

20.9 ± 5.7 < 0.001

Mean g protein/Kg/day a 0.75 ± 0.34 0.94 ± 0.43 0.81 ± 0.28

1.1 ± 0.35 < 0.001

EN-relatedcomplications

Anycomplication

89 (21.9%) NA 29(67.4%)

32(42.6%)

< 0.001

↑ GRV 46 (11.4%) NA 16(36.4%)

19 (25%) < 0.001

Diarrhoea 35 (8.6%) NA 8 (18.2%) 8 (10.5%) 0.01

Vomiting 5 (1.2%) NA 1 (2.3%) 2 (2.6%) 0.59

Aspiration 0 NA 0 1 (1.3%) 0.99

Mesentericischemia

3 (0.7%) NA 4 (9.1%) 2 (2.6%) 0.01

Outcomes


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EN

(63.4%; n = 405)

Total PN

(18.2%; n = 116)

EN-PN

(6.7%; n = 43)

PN-EN

(11.7%; n = 75)

pvalue

Mechanical ventilation 394(97.5%)

79 (68.1%) 40 (93%) 70 (93%) < 0.001

Days on mechanical ventilation 13.2 ± 13.8 7.3 ± 11 21.5 ± 18.3

17.7 ± 21.3

< 0.001

Vasoactive drug support 296(73.3%)

75 (63.6%) 33 (75%) 70(92.1%)

< 0.001

RRT needs 41 (10.1%) 22 (18.6%) 18(40.9%)

16(21.1%)

< 0.001

Respiratory tract infection 102(25.2%)

35 (29.7%) 8 (18.2%) 21(27.6%)

0.48

Catheter-related infections 26 (6.4%) 12 (10.2%) 2 (4.5%) 3 (3.9%) 0.311

Mean ICU stay (days) 13 (8–22) 8 (6–13) 16 (10–38)

16 (10–20)

< 0.001

Mean hospital stay (days) 25 (16–42)

27 (15–47) 30 (17–54)

35 (19–62)

0.012

28-day Mortality 101(24.9%)

27 (23.3%) 16(37.2%)

20 () 0.19


We found differences in illness severity (e.g., SOFA and APACHE II), patient characteristics, patient type,mean calories achieved, and mean protein achieved during and after nutritional support. Adjusting forlength of nutritional support, ICU scores, and nutritional risk scores (i.e., NUTRIC and SGA) asconfounding factors, we found differences between subgroups. Compared with the PN group, patientsreceiving EN were more likely to be admitted for a medical indication (HR: 5.564; 95% CI: 3.013–10.273; P < 0.001) and to require invasive mechanical ventilation compared with the PN subgroup (HR: 6.950; 95%CI: 1.120–7.766; P < 0.001).

Compared with the EN-PN subgroup, the EN subgroup performed better during early EN support (HR:2.313; 95% CI: 1.130–4.763; P = 0.022) and had fewer EN-related complications (HR: 0.264; 95% CI:0.133–0.527; P < 0.001). Compared with PN-EN subgroup, the EN subgroup also needed less vasoactivedrug support (HR: 0.234; 95% CI: 0.089–0.612; P = 0.003) and suffered lower EN-related complication (HR:0.469; 95% CI: 0.259–0.850; P = 0.013) when. Compared with the EN-PN subgroup, the PN subgroup had

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a lower 28-day mortality rate (HR: 0.321; 95% CI: 0.134–0.335; P = 0.02). Compared with the PN-ENsubgroup, the EN-PN had more EN-related complications (HR: 2.983; 95% CI: 1.102–8.017; P = 0.032) andhigher 28-day mortality (HR: 3.149; 95% CI: 1.055–9.398; P = 0.04). Indeed, the EN-PN subgroup showedthe worst 28-day survival among all subgroups during ICU admission (Fig. 2A). Despite not achievingstatistical signi�cance, patients who received EN �rst line (i.e., the EN and EN-PN subgroups) receivedless mean calorie and protein delivery than patients in whom PN was started initially (i.e., the PN and PN-EN subgroups).

There were also differences between groups by survival, with non-survivors having more comorbiditiesand showing greater nutritional risk, illness severity, and need for RRT and vasopressor support (Table 3).Non-survivors also had a higher incidence of mesenteric ischemia and shorter ICU stays, whereassurvivors received more protein and fewer calories while receiving nutritional support (or for 14 days).When we analyzed the 28-day survival, we found that patients admitted because of trauma (11.3%)showed a trend toward better survival than those admitted with either surgical (23.5%) or medical (29.4%)indications (P = 0.003; Fig. 2B). Patients with higher nutritional risk also showed poorer survival, withsurvival rates of 87% and 68% for mNUTRIC scores of 0–4 and > 4, respectively (P < 0.001; Fig. 2C). Noanalysis revealed an association by the time of starting nutritional therapy.

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Table 3Differences in baseline characteristics, nutrition therapy, and outcomes between survivors and non-

survivors.

Survivors

(74.3%; n = 475)

Non-survivorsb

(25.6%; n = 164)

p value


Mean age (years) 59.8 ± 15 67.7 ± 12 < 0.001

Sex (male) 325 (68.4%) 107 (65.2%) 0.45

BMI (Kg·m− 2) 27.8 (27.2–28.3) 27.1 (27.0-29.1) 0.71

Hypertension 194 (40.8%) 87 (53%) 0.007

Diabetes mellitus 118 (24.8%) 46 (28%) 0.41

COPD 68 (14.3%) 42 (25.6%) < 0.001

AMI 68 (14.3%) 26 (15.9%) 0.63

Chronic Liver Disease 23 (4.8%) 9 (5.5%) 0.74

Chronic Renal Failure 44 (9.3%) 24 (14.6%) 0.05

Immunosuppression 41 (8.6%) 32 (19.5%) < 0.001

Neoplasia 89 (18.7%) 48 (29.3%) 0.005

Type of patient Medical 283 (59.6%) 118 (72%) 0.04

Surgery 127 (26.7%) 39 (23.8%) 0.15

Trauma 65 (13.7%) 7 (4.3%) 0.001

APACHE II 19 (14–24) 23 (17–27) < 0.001

SAPS II 47 ± 17 54 ± 18 < 0.001

SOFA (on admission) 6.6 ± 3.3 8.4 ± 3.7 < 0.001

Patient with malnutrition (based on SGA) 36.5% (173) 58.5% (96) < 0.001

mNUTRIC Score 3.8 ± 2.1 5.2 ± 1.7 < 0.001

BMI: Body Mass Index; COPD: Chronic Obstructive Pulmonary Disease; AMI: Acute MyocardialInfarction; APACHE II: Acute Physiology and Chronic Health Disease Classi�cation System II; SAPS:Simpli�ed Acute Physiology Score; SOFA: Sequential Organ Failure Assessment; SGA: SubjectiveGlobal Assessment; mNUTRIC: modi�ed Nutrition Risk in the Critically Ill; EN: Enteral Nutrition; PN:Parenteral Nutrition; ↑ GRV: Elevated Gastric Residual Volume (> 500mL); RRT: Renal ReplacementTherapy; ICU: Intensive Care Unit; LOS: Length of stay. Results are expressed as mean ± standarddeviation, percentage or median and interquartile range (�rst and third quartile). a During theadministration of the whole nutritional therapy or at least in the �rst 14 days of nutritional therapy. bBased on 28-day mortality.

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Survivors

(74.3%; n = 475)

Non-survivorsb

(25.6%; n = 164)

p value

Patient at risk (based on NUTRIC) 39.7% (185) 64.6% (102) < 0.001

Nutrition therapy

Time of initiation of nutritional therapy (h) 27 (18–48) 31 (20–50) 0.23

Type of nutritionalsupport

EN 331 (69.7%) 117 (71.3%) 0.85

PN 144 (30.3%) 47 (28.6%) 0.75

EN-PN 27 (5.7%) 16 (9.8%) 0.12

PN-EN 55 (11.6%) 20 (12.2%) 0.91

Early EN (< 48h) 357 (75.2%) 121 (73.8%) 0.85

Days on nutrition therapy 8 (4–18) 7 (4–12) 0.17

Mean Kcal/Kg/day a 15.6 (15.2–16.4) 15.9 (14.8–16.9) 0.19

Mean g protein/Kg/day a 0.80 (0.78–0.85) 0.75 (0.72–0.85) 0.12

EN-related complications Any complication 111 (23.3%) 39 (23.7%) 0.83

↑ GRV 63 (16.3%) 18 (13.1%) 0.41

Diarrhoea 40 (10.4%) 11 (8%) 0.50

Vomiting 5 (1.3%) 3 (2%) 0.98

Aspiration 1 (0.3%) 0 0.99

Mesentericischemia

2 (0.5%) 7 (5.1%) 0.002

Outcomes

Mechanical ventilation 430 (90.5%) 153 (93.3%) 0.28

Days on mechanical ventilation 13 (12–15) 12 (10–13) 0.12

Vasoactive drug support 337 (70.4%) 137 (83.5%) 0.001


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Survivors

(74.3%; n = 475)

Non-survivorsb

(25.6%; n = 164)

p value

RRT needs 59 (12.2%) 38 (23.2%) 0.001

Respiratory tract infection 124 (26.1%) 42 (25.6%) 0.99

Catheter-related infections 27 (5.9%) 15 (9.1%) 0.15

Mean ICU LOS (days) 13 (8–22) 11 (8–17) 0.006

Mean hospital LOS (days) 32 (19–54) 16 (10–27) < 0.001


In the multivariate analysis, we adjusted for confounders such as the nutritional therapy duration, ICUscore, patient type, and nutritional risk score (i.e., mNUTRIC and SGA). This revealed that older age andhigher mNUTRIC and SOFA scores at ICU admission were positively associated with the 28-day mortality.The EN-PN subgroup also showed a positive association with 28-day mortality. A higher mean caloriedelivery during nutritional therapy was associated with a higher mortality, whereas a higher mean proteindelivery was protective against higher mortality (Table 4).

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Table 4Multivariate analysis* of factors associated with 28-day mortality in patients receiving arti�cial nutritional

therapy during ICU stay.

Hazard ratio (95% Con�dence Interval) p value

Age (years) 1.023 (1.008–1.038) 0.003

Non-trauma patient 1.965 (0.900-4.295) 0.090

SOFA Score 1.096 (1.036–1.160) 0.001

mNUTRIC Score 1.136 (1.025–1.259) 0.015

EN-PN subgroup 2.368 (1.168–4.798) 0.017

Mean Kcal/Kg/day a 1.057 (1.015–1.101) 0.008

Mean g protein/Kg/day a 0.507 (0.263–0.977) 0.042

Renal Replacement Therapy 1.742 (1.174–2.583) 0.063

Vasoactive drug support 1.564 (0.996–2.456) 0.344

* Model adjusted for potential confounders (i.e., age, patient type, illness severity, length of nutritiontherapy, and other signi�cant differences in baseline characteristics, such as sex, comorbidities, BodyMass Index, vasoactive drug support, and renal replacement therapy). SOFA: Sequential Organ FailureAssessment; mNUTRIC: modi�ed Nutrition Risk in the Critically Ill; EN: Enteral Nutrition; PN: ParenteralNutrition.

a During the administration of the whole nutritional therapy or at least in the �rst 14 days ofnutritional therapy.

DiscussionThe results of the present study underline the importance of nutritional therapy and how nutrition-relatedfactors may affect mortality. Some of these factors, such as having a higher SOFA score or higher age,are logically associated with mortality. However, the roles of the mNUTRIC score, the need for PN afterstarting EN, and a higher mean caloric intake during nutritional therapy are �ndings that merit furtherdiscussion. The �nding that a higher protein intake could be associated with lower mortality alsowarrants discussion.

The NUTRIC score was the �rst tool developed speci�cally to assess nutritional risk in patients admittedto ICU. It has been shown to correlate closely with poor outcomes [16, 19], likely related to the inclusion ofboth age and the SOFA score [20]. Hospitalized older patients are certainly known to suffer morecomorbidities, to be at nutritional risk, and to suffer malnutrition, which increase mortality [21]. Thedegree of organ failure is also linked directly to disease severity and the ability to tolerate nutritionaltherapy, with greater organ failure potentially causing gastrointestinal complications, gastrointestinaldysfunction and failure, and inadequate absorption, ultimately leading to malnutrition [22, 23]. This latter

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issue is compounded by the inadequate provision of nutritional therapy during ICU admission, andperhaps most importantly, by excessive in�ammation that may result in poorer nutrient absorption [24,25]. The association of age, the SOFA score, and the NUTRIC score with the 28-day mortality appearsconcordant with the pathophysiology of nutrition in critically ill patients.

The EN-PN subgroup was associated with higher 28-day mortality compared with the other subgroups. Itis certainly plausible that the delay in starting PN, probably due to their clinical condition (i.e., higherseverity) on ICU admission, contributed to the higher mortality rates. However, it is also plausible thatthese patients experienced higher rates of gastrointestinal dysfunction and failure [25, 26]. We alsoshowed, consistent with contemporary literature, that the use of PN is safe and it does not affectmortality directly [27]. PN, alone or combined with EN, may provide higher mean calorie and proteinintakes, which in turn, may improve outcomes.

We also showed that calorie and protein goals, per recommended clinical practice guidelines, were notmet in this study. This was especially true of patients in whom EN was started from the beginning [2–4].Indeed, patients requiring PN after starting EN were more prone to EN-related complications, re�ectingtheir disease severity and di�culty in achieving calorie and protein goals. The latter, together with lowercalorie and protein delivery in the EN-PN subgroup, could be related to the higher mortality experienced bythose patients. Recent contemporary trials have also reported that these goals were not achieved, withevidence that mean protein amounts of only 0.8–1.1 g·kg− 1·d− 1 were delivered, possibly re�ecting thedi�culty inherent in providing nutritional therapy to patients with severe critical illnesses [10–13].However, the calorie goal for the critically ill is somewhat controversial given that permissiveunderfeeding (i.e., 60–70% of the caloric target) appears to be not only safe but also superior in terms ofoutcomes in some ICU populations [28, 29]. A full caloric target (i.e., 90–100%) may not be the optimal inthe early catabolic phase of an illness, and as such, the caloric target should be individualized based onthe patient’s nutritional reserve. However, a caloric intake closer to the target is recommended when thereis a risk of malnutrition or when malnutrition and a poor nutritional reserve is present [30, 31]. Moststudies to date have also used formulas to calculate calorie goals and have not considered any non-nutritional calorie intake (e.g., glucose, citrate, or propofol) [32]. Achieving caloric goals based on 70% ofenergy needs, as measured by indirect calorimetry, seems to offer survival advantages for ICU patients[33]. Thus, the association of a higher calorie intake with 28-day mortality is probably due to the highcalorie goal, which may ultimately be associated with overfeeding [34].

Stress catabolism during the early phase of critical illness results in a loss of protein mass from muscle,contributes to sarcopenia, and ultimately leads to di�cult recovery and poorer outcomes [29]. By contrast,a high-protein intake in the early phase of disease may decrease the acute negative protein balance andmuscle loss while improving functional recovery [35, 36]. Indeed, the increase in protein synthesis duringthe catabolic phase combined with adequate protein intake may help to reduce the negative proteinbalance [37, 38]. This may explain our �nding of improved survival with a higher mean protein intakeduring arti�cial nutritional therapy.

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Our study has several limitations, mainly related to its observational design, the heterogeneity ofparticipants, and the di�culty in obtaining the correct macronutrient doses based on clinical practiceguidelines during ICU admission. However, the multicenter nature, large sample size, clinical setting(re�ecting real practice by ICU physicians delivering nutrition therapy), and long follow-up (14 days afterICU admission) are important strengths. Given the confounding in�uence of illness severity, patient type,and other potential confounders, we sought to account for these in our analyses. For example, this isimportant regarding the type of patient: trauma patients in our population experienced lower mortality,which may ultimately be explained by their characteristics (i.e., younger age, fewer comorbidities, and abetter nutritional statuses) [24]. We also strati�ed patients by the type of arti�cial nutritional therapy toidentify differences. We believe that the novelty of this research is in the combination of all thesemethods together with all the combined reported observations in the multivariable analysis. Our resultsregarding mean calorie and protein intakes come to the fore as areas that merit further analysis. We havean analysis planned to assess the adequacy of when macronutrient intake occurred.

ConclusionsIn summary, we showed that higher nutritional risk, greater organ failure severity, and older age may benutrition-related factors that are associated with increased mortality. Regarding the type of nutritionaltherapy received, those patients needing PN after starting EN may represent a high mortality risksubgroup, probably due to greater illness severity and the presence of gastrointestinal failure, which alsocauses problems in giving appropriate nutritional therapy. Mortality may be lowered by providing a highermean protein intake and increased by an excessive mean caloric intake. These �ndings, in turn, indicatethat macronutrient delivery may have a prominent role in ICU outcomes.

AbbreviationsEN, Enteral nutrition; ENPIC, Evaluation of Nutritional Practices in the Critical Care; ICU, Intensive care unit;LOS, Length of stay; NUTRIC, Nutrition Risk in the Critically Ill; PN, Parenteral nutrition; RRT, Renalreplacement therapies; SAPS, Simpli�ed Acute Physiology Score; SGA, Subjective Global Assessment;SOFA, Sequential Organ Failure Assessment.

Declarations

Acknowledgments:We thank all the members of the ENPIC Study Group who participated in the meeting held in Madrid onOctober 26–27, 2017 for their contribution to a consensus in drafting the database used in the presentstudy.

The following list comprise the members of the ENPIC (study of the Evaluation of Nutritional Practices Inthe Critical care patient) collaboration, and should be acknowledged as collaborating authors:

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Lluís Servia-Goixart, Javier Trujillano-Cabello, Joan Escobar-Ortiz, Neus Montserrat-Ortiz, Amalia Zapata-Rojas (H. Universitari Arnau de Vilanova, Lleida); Teodoro Grau-Carmona, Iris Bautista-Redondo, Ana Cruz-Ramos, Laura Diaz-Castellanos, Miriam Morales-Cifuentes, Montserrat Plaza- Bono, Juan Carlos Montejo-Gonzalez, Susana Temprano-Vazquez, Veronica Arjona-Diaz (H. Universitario 12 de Octubre, Madrid);Carlos Garcia-Fuentes, Carolina Mudarra-Reche, Maria Orejana-Martin (H. Universitario 12 de Octubre, UCIde Trauma y Emergencia, Madrid); Juan Carlos Lopez-Delgado, Africa Lores-Obradors, Laura Anguela-Calvet, Gloria Muñoz-Del Río, Pamela Alejandra Revelo-Esquibel, Henry Alanez-Saavedra, Pau Serra-Paya,Stephani Maria Luna-Solis, Alvaro Salinas-Canovas (H. Universitari Bellvitge, L’Hospitalet del Llobregat,Barcelona); Fernando De Frutos-Seminario, Oriol Rodriguez-Queralto (H. Universitari Bellvitge, UnidadCoronaria, L’Hospitalet del Llobregat, Barcelona); Carlos Gonzalez-Iglesias, Monica Zamora-Elson (H. deBarbastro, Barbastro, Huesca); Eugenia de la Fuente-O'Connor (H. Universitario Infanta Sofía, SanSebastian de los Reyes, Madrid); Carlos Seron- Arbeloa, Nestor Bueno-Vidales (H. San Jorge, Huesca);Rayden Iglesias-Rodriguez (H. General de Granollers, Barcelona); Ana Martin-Luengo (H. Rio Hortega,Valladolid); Angel Sanchez-Miralles, Enrique Marmol-Peis, Miriam Ruiz-Miralles, Maria Gonzalez-Sanz,Arantzazu Server-Martinez, (H. Sant Joan d’ Alacant, Alicante); Belen Vila-Garcia (H. Infanta Cristina deParla, Madrid); Carol Lorencio-Cardenas (H. Universitari Josep Trueta, Girona); Laura Macaya-Redin,Raquel Flecha-Viguera, Sara Aldunate-Calvo (H. de Navarra, Pamplona); Jose Luis Flordelis-Lasierra, IreneJimenez-del Rio, Jose Ramon Mampaso-Recio, Jose Manuel Rodriguez-Roldan (H. Universitario SeveroOchoa, Leganés, Madrid); Rosa Gastaldo-Simeon, Jose�na Gimenez-Castellanos (H. Manacor, Mallorca);Juan Francisco Fernandez-Ortega, Juan F Martinez-Carmona, Esther Lopez-Luque, Ane Ortega-Ordiales(H. Regional Universitario Carlos Haya, Málaga); Monica Crespo-Gomez, Victor Ramirez-Montero, EstherLopez-García, Arturo Navarro-Lacalle (H. Universitari Doctor Peset, Valencia); Pilar Martinez-Garcia, MariaInmaculada Dominguez-Fernandez (H. Universitario de Puerto Real, Cadiz); Paula Vera-Artazcoz, MartaIzura-Gomez, Susana Hernandez-Duran (Hospital de la Santa Creu i Sant Pau, Barcelona); Mª LuisaBordeje-Laguna, Esther Mor-Marco, Yaiza Rovira-Valles, Viridiana Philibert (H. Universitari Germans Trias iPujol, Badalona, Barcelona); Maravillas de las Nieves Alcazar-Espin, Aurea Higon-Cañigral (H. G.Universitario Morales Meseguer, Murcia); Enrique Calvo-Herranz, Diego Manzano-Moratinos (H.Universitario de Getafe, Madrid); Esther Portugal-Rodriguez, David Andaluz-Ojeda, Laura Parra-Morais,Rafael Citores-Gonzalez, Maria Teresa Garcia-Gonzalez, Gloria Renedo Sanchez-Giron (H. ClínicoUniversitario de Valladolid; Elisabeth Navas-Moya, Carles Ferrer-Pereto, Cristina Lluch-Candal, JessicaRuiz-Izquierdo, Silvia Castor-Bekari (H. Mutua Terrassa, Barcelona); Cristina Leon-Cinto (H. RoyoVillanova, Zaragoza); Itziar Martinez de Lagran, Juan Carlos Yebenes-Reyes (H. de Mataro, Barcelona);Beatriz Nieto-Martino, Clara Vaquerizo-Alonso (H. Universitario de Fuenlabrada, Madrid); SusanaAlmanza-Lopez, Sonia Perez-Quesada, Jose Luis Anton-Pascual (H.G. Universitario de Alicante); JudithMarin-Corral, Maite Sistachs-Baquedano, Maria Hacer-Puig, Marina Picornell-Noguera (H. del Mar,Barcelona); Lidon Mateu-Campos, Clara Martinez-Valero, Andrea Ortiz-Suñer (H.G. Universitario deCastellón); Beatriz Llorente-Ruiz, María Cristina Martinez-Diaz, Maria Trascasa- Muñoz De La Peña, DiegoAnibal Rodriguez-Serrano (H. Príncipe de Asturias, Alcalá de Henares, Madrid); Leticia Fernandez-Salvatierra, Mireia Barcelo-Castello, Paula Millan-Taratiel (H. Clínico Lozano Blesa, Zaragoza); AntonioTejada-Artigas, Ines Martinez-Arroyo, Pilar Araujo-Aguilar, Maria Fuster-Cabre, Laura Andres-Gines, Sonia

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Soldado-Olmo (H. Miguel Servet, Zaragoza); Eva Mª Menor-Fernandez, Lucas Lage-Cendon, AlbertoTouceda-Bravo (H. Álvaro Cunqueiro, Vigo); Laura Sanchez-Ales, Laura Almorin-Gonzalvez (H. Plató,Barcelona); Maria Gero-Escapa, Esther Martinez-Barrio, Sergio Ossa-Echeverri (H. Universitario deBurgos); Diana Monge-Donaire (Hospital Virgen de la Concha, Zamora).

Authors’ contributions:JCLD, TGC and LSG conceived, designed and coordinated the study. All authors collected the data duringthe study period and participated in the revision. TGC, JCLD and JTC performed the statistical analysisand developed the �rst draft of the manuscript. All authors were involved in the interpretation of theresults, critically revised the manuscript and approved the �nal version.

Funding:The present research was granted by the Spanish Society of Nutrition and Metabolism (SENPE; SociedadEspañola de Metabolismo y Nutrición).

Availability of data and materials:The datasets used and/or analyzed during the current study are available from the ENPIC StudyInvestigators on reasonable request.

Ethics approval:This study was approved by a central Institutional Ethics Committee (Comité d’Ètica i Assajos Clínics deHospital Universitari de Bellvitge; Barcelona, Spain) with registered number PR401/17.

Declarations:All the authors declare that they have no con�icts of interest in regard to the subject of this manuscript.

Consent for publication:Not applicable.

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Figures

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Figure 1

Study �ow chart

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Figure 2

Kaplan–Meier curves and log-rank test. The �gures show survival by route of nutrition therapy (A), patienttype (B), and nutritional risk (C). Nutritional risk was based on the modi�ed Nutrition Risk in the CriticallyIll (mNUTRIC) score.

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